RSV infection is known to be transmitted through direct contact with an infection source but not through inhalation (Bont L., Paediatr. Respir. Rev., 2009, 10, Suppl 1:16-17). Consistent with this mechanism, the inoculation of RSV to the human nose or eyes has been reported to result in viral replication, during an incubation period of 4 to 5 days, which may then spread infection to the lower respiratory tract (Collins P. L., and Graham B. S., J. Virol., 2008, 82:2040-2055). In BALB/c mice instillation of RSV into the eye leads to an eye infection, followed by inflammation and subsequently to eye-to-lung viral transmission, resulting in respiratory pathology (Bitko V., Musiyenko A. and Bark S. J. Virol., 2007, 81:783-790).
Infection by RSV is a well known cause of respiratory disease in both infants and young children and has the potential to cause severe lung disease, including bronchiolitis and death. RSV infection has been cited as a central concern in the care of high-risk, pre-term infants (Bauer G., Bossie L. et al., Arch. Argent. Pediatr., 2009, 107:111-118). It remains unclear and controversial whether severe RSV infection in early infancy precipitates the development of asthma in later life or whether RSV bronchiolitis precedes asthma in children who are susceptible to becoming asthmatic (Mailaparambil B., Grychtol R. et al., Inflamm. Allergy Drug Targets, 2009, 8: 202-207). Recently the standard of care for treating RSV disease has been re-defined by the licensing and introduction of a monoclonal antibody therapeutic, palivizumab, a humanized mAb against the RSV F protein, which provides passive immunity against the virus.
Much more uncertainty exists regarding the prevalence and significance of RSV infections in the elderly. This arises, not least, because of the difficulty of differentiating infection by RSV from infection by influenza and the fact that both diseases show a similar prevalence by season. However, the recent development of new methods for detecting viruses has allowed research workers to investigate whether RSV infection is present in adults. This work has led to the conclusion that a significant proportion of upper respiratory tract infections (URTI) in adults is caused specifically by RSV (Caram L. B., Chen J. et al., J. Am. Geriatr. Soc., 2009, 57:482-485). Furthermore, in patients diagnosed with COPD, persistent RSV detection was associated with airway inflammation and accelerated decline in FEV(1) (Wilkinson T. M., Donaldson G. C. et al., Am. J. Respir. Crit. Care, 2006, 173:871-876). In addition RSV infection is also commonly regarded as being a significant cause of exacerbations in patients who suffer from asthma (Hansbro N. G., Horvat J. C. et al., Pharmacol. Ther., 2008, 117:313-353). Consistent with these clinical observations, RSV infection has been reported to produce airways hyper-responsiveness in mice and the persistence of RSV RNA correlated significantly with pulmonary function abnormalities (Estripeaut D., Torres J. P. et al., J. Infect. Dis., 2008, 198:1435-1443).
In addition to the established view that RSV is a significant cause of morbidity and mortality in young children, recently work suggests that it is also an important factor contributing to unwanted effects in patients suffering from chronic respiratory diseases. While the introduction of palivizumab has established a new standard of care, such therapy, using monoclonal antibodies, remains very expensive and effective new medicines to treat RSV-induced lung disease are still urgently required. Furthermore, given the mode of transmission of the pathogen, there is a significant opportunity to develop therapies that prevent and/or treat viral infection by targeting those mucosal surfaces which it attacks.
RSV exploits a variety of mechanisms to suppress innate cellular immunity responses and to maintain optimal growth in the infected host cells, represented by the suppression of type I interferon (IFN) and of interferon α and interferon β induction (Spann K. M., et al., J. Virol. 2005, 79:5353-5362). In this regard, RSV viral surface proteins have been implicated in the reduction of Type 1 interferon expression by signalling through the Toll-like receptor pathway (Oshansky C. M. et al., Viral Immunol., 2009, 2:147-161). In addition, RSV infection has been reported to decrease the cellular levels of key members of the interferon signalling pathway, including IKKε and TRAF3 (Sweden S. et al., J. Virol., 2009, 83:9682-9693).
Infection by RSV has been documented to up-regulate the expression of IL-1β, IL-6, IL-8, TNF-α, MIP1a, RANTES, and ICAM-1 in epithelial cells: the main targets of RSV in vivo. The elevated expression of these inflammatory molecules during RSV infection has been attributed to the activation of nuclear factor-κ B (Kong et al., BBRC 2003, 306:616-622). In this regard, RSV infection is believed to induce a time-dependent RelA phosphorylation during which reactive oxygen species are produced in parallel (Jamaluddin M. et al., J. Virol., 2009, 83:10605-10615) that are potent oxidative stressors of the intracellular glutathione redox state. In human airway epithelial cells this activates signals that increase the production of cytokines and chemokines (Mochizuki H. et al., Inflammation, 2009, 32:252-264). In A549 cells RSV has been reported to activate both ERK-1 and ERK-2 pathways within 5 min of infection, leading to the inhibition of pathways that decrease RSV infection (Kong X., et al., FEBS Lett., 2004, 559:33-38). P38MAPK activation by RSV was also confirmed in primary bronchial epithelial cells (Signh D., et al., Am. J. Physiol. Lung Cell. Mol. Physiol., 2007 293(2):L436-45.). Furthermore, RSV infection has been reported to increase the phosphorylation of PKC α/β in monocytic cells (Ennaciri J. et al., J. Leukoc. Biol., 2007, 81:625-631) and is associated with the induction of anti-apoptotic effects through a PI3 kinase-dependent mechanism (Thomas K. W. et al., J. Biol. Chem., 2002, 277:492-501).